DESCRIPTION Multiple mechanisms has been postulated to cause motor neuron (MN) in amyotrophic lateral sclerosis (ALS) including excitotoxicity and oxidative stress. The proposed studies test the hypothesis that oxyradical accumulation in mitochondria plays a major role in the pathogenesis of ALS by promoting membrane lipid peroxidation, disruption of ion homeostasis and apoptosis in motor neurons. Many cases of autosomal dominant familial ALS result from missense mutation in Cu/Zn-SOD. I will employ a MN-like cell line and transgenic mouse model of ALS in which expression of human CU/Zn-SOD gene result in MN death generation and a clinical profile similar to human ALS, to elucidate mechanisms of MN death relevant to ALS. I propose that over-expression of mitochondrial MnSOD can protect MNs against apoptosis, by suppressing mitochondrial oxyradical production and membrane lipid peroxidation. The proposed research will elucidate mechanisms of MN degeneration of MN degeneration relevant to the pathogenesis of ALS, and will identify potential preventative and therapeutic approaches for human ALS patients.